PROJECT SUMMARY/ABSTRACT Humans are colonized with diverse microbial communities, collectively called the commensal microbiota, that influence a wide array of biological processes. Recent studies demonstrate that in addition to their roles in nutrition, immunity and metabolism, the commensal microbiota also plays a fundamental role in the development and function of the nervous system, in addition to several complex host behaviors. The proposed research training program aims to uncover the mechanisms underlying the interaction between specific commensal microbes and the nervous system, and to elucidate the impact of these relationships on host physiology. Specifically, the proposed research will examine the role of commensal microbes on host serotonin (5-hydroxytrypatmine, 5-HT) metabolism, with aims to define the specific steps of the 5-HT pathway that are affected by commensal microbes, identify the particular microbial species and factors that affect host 5-HT, and apply these microbial 5-HT modulators toward ameliorating symptoms in models of 5-HT-related disease. Findings from these studies will advance our current understanding of how the commensal microbiota affects health and disease, and will further explore the innovative prospect of developing novel, microbe-based therapeutics, which can be readily modified for better function, regulatory control, targeting and delivery. The proposed studies on the interaction between the commensal microbiota and nervous system fills a novel area of multidisciplinary research that integrates not only neurobiology and microbiology, but also biochemistry (in the dissection of molecular alterations in the 5-HT pathway), chemical engineering (in the nanofabrication of microfluidic devices for high-throughput confinement, cultivation and functional screening of endogenous species of the microbiome) and molecular and behavioral neuroscience (in the investigation of pathologies seen in mouse models of serotonin-deficiency). My proposed training will span five years of independent research as a Senior Research Fellow at the California Institute of Technology. This title is typically reserved for individuals with previous post-doctoral experience and serves as a transitional stage toward advancing into a junior faculty position. Approximately one year after the award is conferred, I will recruit one full-time technician, with significant previous experience in laboratory research. I will also begin mentoring up to two biology or chemistry undergraduate students per year through Caltech's summer research program.